Perspectives on Immunotherapy in the Treatment of Advanced NSCLC: A Stakeholder Interchange Report

Immunotherapy Treatment Landscape in Advanced NSCLC

Lung cancer is the leading cause of cancer-related mortality in the United States.¹ Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers.² Survival varies according to the stage and extent of the cancer. The 5-year survival rates for men with localized and distant stages of NSCLC are 59% and 7%, respectively, while in women, they are 70% and 11%, respectively.¹ Of the 3 main types of NSCLC, adenocarcinoma accounts for 40% of cases, squamous cell carcinoma for about 25%, and large cell carcinoma for about 10%.³ While cigarette smoke is the leading risk factor associated with the development of lung cancer, several familial, behavioral, environmental, and genetic risk factors have been identified.⁴

Treatment Approaches

The treatment approaches for NSCLC vary depending on the stage of the disease. In early-stage NSCLC, surgery is often considered as the primary choice and offers the best chance for a cure, particularly for patients with stage I or II disease. However, the patient’s cardiopulmonary reserve must be assessed before surgery is performed.⁴

Radiation therapy plays a significant role in the treatment of NSCLC and can be used in various stages. It can be offered definitively for patents with locally advanced disease, with the aim of providing curative treatment. Additionally, radiation can be incorporated into the neoadjuvant or adjuvant settings, especially for patients with positive surgical margins. In cases of incurable metastatic disease, radiation also can be used as part of palliative management.⁴

Systemic therapy, including chemotherapy, is another treatment option. Platinum-based chemotherapy is recommended when patients are ineligible for targeted therapy or immunotherapy. It can be administered in the neoadjuvant, adjuvant, or concurrent setting with radiation therapy.⁴

Targeted therapy and immunotherapy are specifically designed for advanced or metastatic NSCLC.⁴ These treatments have higher response rates and are often better tolerated than is chemotherapy.⁴ Targeted therapy is dependent on the presence of specific gene mutations, while immunotherapy is used in patients whose tumors express a high amount of PD-L1 (≥ 50%) but do not harbor actionable molecular biomarkers.⁴

Combining immunotherapy with chemotherapy is also an approach that may be employed. Ultimately, the treatment path for NSCLC is determined by the patient’s clinical presentation, stage of the disease, and individual factors. A multidisciplinary approach involving discussions among health care professionals is often necessary to determine the most appropriate treatment strategy for each patient.

Principles of Cancer Immunotherapy

Principles of cancer immunotherapy revolve around the concept of the cancer immunity cycle, based on the idea that the immune system of cancer patients is not necessarily compromised and remains largely intact. By modifying and enhancing specific steps within this cycle, there is a significant opportunity to activate the immune system and combat cancer.

The cycle begins with the release of cancer antigens from cancer cells, often achieved through treatments like chemotherapy or radiation therapy. These antigens are then presented to antigen-presenting cells, such as dendritic cells. Through a process known as priming activation, T cells in the lymph nodes are stimulated, and they proliferate. These activated T cells enter the bloodstream and infiltrate the tumor, where they can recognize tumor-specific antigens. Upon activation, particularly of CD8-positive T cells, the immune cells can effectively target and kill cancer cells. The activation of costimulatory pathways is also crucial in this process.

Types of Cancer Immunotherapy

Based on these principles, various types of cancer immunotherapy have emerged; primarily, T cell–based approaches have demonstrated success. One prominent example is immune checkpoint inhibitors, which target the natural regulators responsible for dampening immune cell activity. Immune checkpoint proteins, such as PD-1 and PD-L1, interact with each other to activate coinhibitory pathways that suppress T-cell activity. Blocking these interactions forms the mechanism of action of immune checkpoint inhibitors.

Additionally, adoptive T-cell transfer allows the utilization of tumor-specific antigens. T cells can be engineered ex vivo, modifying their extracellular and intracellular domains to enhance their sustained activity. Chimeric antigen receptor (CAR) T-cell therapy is one such example of treatment involving engineered T cells.

Cancer vaccines also play a role, particularly with the aid of artificial intelligence. By comparing the genetic sequences of tumor cells and normal cells, advanced algorithms can identify potent new antigens. This information enables the development of personalized vaccines tailored to the individual patient’s tumor characteristics.

Immune Checkpoint Inhibitors in Lung Cancer

The following summary highlights the FDA-approved immune checkpoint inhibitors for NSCLC. Beginning in 2015 results from the, CheckMate 057 (NCT01673867) and CheckMate 017 (NCT01642004) studies led to the approval of nivolumab in the second-line setting. In 2016 findings from, the KEYNOTE studies, including KEYNOTE-010 (second-line setting; NCT01905657) and KEYNOTE-024 (first-line setting for PD-L1 ≥ 50%; NCT02142738) studies, resulted in the approval of pembrolizumab in the first-line setting. Atezolizumab gained initial approval in the second-line setting after review of findings from the OAK study (NCT02008227). In 2018, the IMpower150 study (NCT02366143) resultsestablished atezolizumab in combination with chemotherapy and bevacizumab for first-line treatment. Findings from the KEYNOTE-407 study (NCT02775435) demonstrated efficacy for squamous NSCLC, while those of the KEYNOTE-189 study (NCT02578680) showed benefits in nonsquamous NSCLC. The PACIFIC trial (NCT02125461) results wererelevant to the nonmetastatic setting. Further, results from the KEYNOTE-042 (NCT02220894), IMpower130 (NCT02367781), and IMpower110 (NCT02409342) trials provided insights into first-line treatment options for patients with PD-L1 expression. Combination therapies, such as those used in the CheckMate 227 (NCT02477826) and CheckMate 9LA (NCT03215706) studies, explored the benefits of adding limited cycles of chemotherapy to anti-CTLA4 and anti–PD-1 treatments. In 2021, cemiplimab was approved for first-line of NSCLC involving a PD-L1 score of at least 50%. The POSEIDON regimen (NCT03164616) described in 2022 combined anti–PD-L1 and anti-CTLA4 with chemotherapy, while the EMPOWER-Lung 3 trial (NCT03409614) published in 2023 examined cemiplimab plus chemotherapy for both squamous and nonsquamous NSCLC. Determining the best first-line treatment involves considering factors beyond the tumor proportion score, and the results of multiple studies have shown that immune checkpoint inhibitors are superior, or at least noninferior, to chemotherapy.

Priorities in the Management of Lung Cancer

Certain priorities come into focus in the management of lung cancer, including the first-line treatment landscape, particularly regarding the approximately 60% response rate observed in current therapeutic approaches. This leaves a proportion of patients who do not respond to standard treatments, which leads to disappointment and a need for alternative strategies. Consequently, second-line treatment options emerge as a priority, “[as] most of our efforts are focused in the neoadjuvant perioperative space”, explained Thomas Stinchcombe, MD.

It is essential to highlight the significance of testing for other mutations, such as in ALK. Notably, the use of targeted therapies alone has yielded impressive results, with 5-year survival rates exceeding 50%. Consequently, comprehensive testing is crucial; however, there remains a challenge in ensuring that the broader medical community recognizes the importance of testing the remaining 25% of patients who are currently not being tested. Paul A. Bunn Jr, MD, FASCO, FACP, FAAAS, stressed that testing is imperative, and it appears that no health care provider in academic medicine has successfully devised a strategy to encourage the community to test these remaining patients.

One suggestion Stinchcombe had was increasing the utilization of blood-based testing. The primary advantage of utilizing blood-based testing in the management of lung cancer is its streamlined and accessible nature. Unlike other testing methods that require involvement from the pathology department or invasive procedures, blood-based testing offers a convenient workaround. The oncologist has direct control over this process, eliminating the need for intermediaries. When blood samples are collected from the patient, they are sent directly to the laboratory for analysis. This simplified pathway empowers oncologists and ensures a more efficient and expedited testing process.

The importance of testing in lung cancer management cannot be understated, particularly in larger cities like Memphis, Tennessee; and Atlanta, Georgia. “I’m surprised [that health care professionals who] I talkto do not prioritize liquid biopsies for patients [when tissue samples are unavailable], commented Benjamin Levy, MD. He suggested that performing liquid biopsies on every patient with an advanced lung cancer diagnosis is an essential practice. The question arises: Why not implement liquid biopsies as a routine procedure for these patients? It is crucial to recognize the immense value and potential impact that liquid biopsies can have in guiding treatment decisions and improving patient outcomes.

Cemiplimab in Clinical Practice

In the CheckMate 227 trial, the efficacy and safety of various treatment regimens were evaluated in patients with advanced NSCLC.5 It specifically focused on patients with high levels of tumor mutational burden and tumor expression of PD-L1.⁵ The trial has yielded intriguing results, prompting further investigation into the potential benefits of combining anti-CTLA4 and anti-PD-1 therapies. In 2021, results of the EMPOWER-Lung 1 study (NCT03088540) demonstrated the efficacy of a new drug called cemiplimab in the first-line treatment of patients with PD-L1 expression of 50% or higher. Although no direct comparison was made, the efficacy of cemiplimab appeared comparable to that noted in the KEYNOTE-024 trial. The EMPOWER-Lung 3 study (NCT03409614) assessed the efficacy of combining cemiplimab with chemotherapy for both nonsquamous and squamous NSCLC. Furthermore, in 2022, the POSEIDON regimen emerged, combining anti–PD-L1 and anti-CTL4 therapies with chemotherapy. This ongoing investigation aims to expand treatment options and improve outcomes for patients.

To incorporate a drug like cemiplimab into clinical practice, a systematic evaluation is necessary. Initiating its use on a limited number of patients allows for an assessment of its efficacy and a comparison with other existing treatments, such as pembrolizumab. However, the decision to adopt cemiplimab on a broader scale hinges upon pivotal factors such as the demand from payers, as their willingness to cover the costs associated with cemiplimab impacts its accessibility. Additionally, considerations related to cost savings for the pharmacy play a significant role in determining the feasibility of incorporating cemiplimab into the treatment regimen. A comprehensive evaluation that encompasses these aspects is essential in making informed decisions regarding the utilization of cemiplimab in clinical practice.

From a mechanistic perspective, the drugs under consideration exhibit similarities and can be viewed as interchangeable. However, when evaluating the trial data, notable distinctions emerge. For instance, certain drugs, such as cemiplimab, did not demonstrate positive results in the first-line setting, whereas pembrolizumab exhibited favorable outcomes. These divergent trial findings suggest potential differences among these drugs, possibly attributed to variations in their binding epitopes or nuances in their drug development processes. Nevertheless, whether these variances significantly impact the ultimate treatment outcome remains uncertain. In clinical practice, it is prudent to rely on trial data when making treatment decisions. If the trial data demonstrate positive results for a specific drug in a particular setting, it is advisable to follow the evidence and consider its use accordingly. For example, nivolumab is not considered a candidate for first line–treatment prescriptions, as it not approved for such use.

Given the financial challenges associated with drug pricing and margins within health systems, a pilot study has been initiated in the field of lung cancer to assess the potential cost-effectiveness of cemiplimab compared with that of pembrolizumab. This study aims to evaluate the relative economic implications of utilizing cemiplimab as a treatment option, considering factors such as drug pricing, reimbursement, and overall health care costs. By conducting this pilot study, valuable insights can be gained regarding the financial viability and potential cost savings associated with cemiplimab in comparison with pembrolizumab, thus informing future decision-making processes within the health care system.

The primary concern lies in the reimbursement aspect, where the ultimate significance lies in whether the cost difference between the 2 treatments translates into differential reimbursement rates. While cost-effectiveness is a crucial consideration, if the difference in reimbursement remains unchanged or comparable between the 2 options, the potential cost advantage of 1 treatment over the other may not yield practical benefits. Thus, achieving a favorable reimbursement structure becomes a critical factor in determining the true value and feasibility of utilizing a less expensive treatment option.

In the clinical practice of Jun Zhang, MD, PhD, the choice between cemiplimab and other treatment options holds significant importance. Zhang is currently involved in a translational study that investigates the impact of the microbiome on immunotherapy adherence. To ensure unbiased data collection, he has incorporated cemiplimab as a treatment option along with pembrolizumab or atezolizumab. Zhang has observed several positive attributes with continued use of cemiplimab. He affirmed that with increased usage, the drug displays favorable characteristics, emphasizing its precise mechanism of action and the drug’s fully human antibody composition. Moreover, he noticed a smoother experience in administering the drug, indicating enhanced clinical outcomes in his practice. His firsthand experience led him to appreciate the efficacy and favorable qualities of cemiplimab.

Importance of Lung Cancer Screening

Lung cancer screening plays a vital role in negative aspects of identifying suitable candidates for immune treatment. It is crucial to have a clear understanding of negative selection before administering immune therapies.

Negative selection involves determining the absence of specific biomarkers such as EGFR and ALK, along with the inclusion of other relevant biomarkers. This testing is essential for guiding treatment decisions, yet it often does not receive sufficient attention. Despite advances, there is still a surprising lack of universal adoption of liquid biopsies for all patients with biopsy-proven lung cancer. Negative selection testing can ensure that patients receive appropriate immune treatments, and it is an integral part of the comprehensive testing process.

“Unfortunately, there is still a significant gap in genotyping lung cancer patients, with only 75% undergoing next-generation sequencing (NGS) testing,” said Bunn. This underutilization of genotyping is inexcusable, as evidenced by the data presented by the Measurable Residual Ddisease Partnership and Alliance in Acute Myeloid Leukemia Clinical Treatment 3 years ago. The data revealed that, at that time, only 50% of patients treated at US Oncology were receiving NGS testing. The need to improve genotyping rates and broaden the scope of comprehensive testing remains a crucial focus in lung cancer management.

NSCLC Prognostic Biomarkers

Predictive molecular biomarkers include ALK rearrangements, BRAF point mutations, and EGFR mutations, among others. PD-L1 expression is the predictive immune biomarker. Molecular testing for actionable oncogenic mutations should be known before starting systemic therapy with immune checkpoint inhibitors in patients with advanced NSCLC, if clinically feasible.⁴

NSCLC features prognostic biomarkers, particularly in the context of 2 groundbreaking therapeutic modalities: targeted therapy and immunotherapy. Testing is recommended to assess whether patients are eligible for targeted therapies or immunotherapies.

There are currently 10 FDA-approved targeted therapies.Foremost among involved biomarkers are oncogenic driver mutations. Regarding immunotherapy, the expression of PD-L1 serves as a critical determinant for selecting either monotherapy or combination therapy. Additionally, the tumor burden, tissue burden, and microsatellite instability play pivotal roles in the tumor agnostic pattern. Consequently, it is imperative to ascertain actionable oncogenic mutations through molecular testing, ideally prior to commencing systemic treatment for patients with NSCLC. Notably, the treatment protocols for NSCLC primarily hinge upon the stage of the cancer.

Monitoring Progression

One of the primary clinical challenges physicians encounter is the accurate assessment of disease progression in patients. Exceptionalresponders present a unique situation, as identifying true progression within the clinical setting remains a daunting task. This issue significantly impacts the decision-making process for enrolling patients in second-line trials, as it is crucial to avoid prematurely discontinuing immune checkpoint inhibitor therapy unless there is clear evidence of its ineffectiveness. Strategies such as PET scans or consolidative radiation therapy targeting oligoprogressive sites can be employed to aid in evaluating disease status. However, situations may arise in which PET scan results present a complex scenario, as evidenced recently whenmultiple sites unexpectedly exhibited increased metabolic activity. Such instances pose challenges in determining the appropriate course of action based on the available information.

Currently in clinical practice, Response Evaluation Criteria in Solid Tumors (RECIST) serve as a common tool for evaluating tumor response and guiding treatment decisions. However, the applicability of RECIST in determining whether to continue or discontinue therapy can be controversial, particularly when considering patients who exhibit some degree of tumor growth while still benefiting from treatment. The discrepancy arises when RECIST-defined progression does not align with the clinical judgment of health care providers. In these cases, the decision to halt therapy based solely on RECIST is unlikely, as clinicians prioritize patient well-being and individual circumstances over rigid response assessment guidelines. Although RECIST provide a standardized framework, their direct impact on clinical decision-making is limited, and health care professionals often take a more comprehensive approach in assessing disease progression and determining the appropriate course of action.

When assessing a patient who demonstrates subjective improvement or experiences a significant positive impact on their quality of life despite radiographic evidence of disease progression, the clinical decision-making process becomes highly nuanced. The conventional treatment paradigm, based solely on radiographic assessments, may not adequately capture the individual patient’s experience. In such cases, experienced health care providers rely on their clinical judgment and comprehensive evaluation of the patient’s overall well-being. Objective measures like PET scans may indicate disease progression, yet the physician must consider the patient’s personal circumstances and treatment goals. It becomes a delicate balance between objective radiographic findings and the patient’s reported positive response and functional improvement. These situations require careful consideration, as switching to alternative therapies with potentially higher toxicity may not align with the patient’s overall benefit and satisfaction. Ultimately, the approach to managing such patients requires a personalized assessment, weighing the clinical data along with the patient’s unique experiences and treatment outcomes.

Duration of Therapy

The issue of determining when to discontinue or modify therapy in the context of disease progression remains a challenge in clinical practice. The lack of clear criteria for defining progression adds complexity to treatment decision-making. As mentioned previously, the focus should extend beyond objective data and radiographic findings to encompass the patient’s individual experience and goals.

Further research and the development of validated criteria are needed to provide more objective measures of disease progression that align with the patient’s clinical status and subjective experience. Such criteria would aid in optimizing treatment decisions and would ensure that patients receive appropriate interventions based on their individual needs and preferences.

The interpretation of radiographic findings and the emphasis on minor differences in PET scans can sometimes divert valuable time and attention from discussions involving important aspects of patient care. This situation highlights the need for a more efficient and effective system that focuses on meaningful discussions with patients. The circulating tumor DNA (ctDNA)test provides precise and tailored information about a patient’s disease and treatment response. Identifying ctDNA negativity can help determine the suitability of immunotherapy and aid in treatment decisions. Implementing routine ctDNA testing may improve prognostication, optimize patient care, and streamline discussions with patients, enhancing overall patient management.

Patient education plays a vital role in helping individuals understand the concept of disease progression and its implications. Providing clear and accurate information to patients about how to interpret their medical reports and radiographic findings can alleviate anxiety and empower them to make informed decisions about their treatment journey.

However, it is important to educate patients about the limitations of certain diagnostic measures, such as radiographic assessments, to help manage their expectations and prevent unnecessary distress. It is important to emphasize that radiographic findings alone may not always reflect the full clinical picture or dictate treatment decisions. Engaging in open and honest discussions with patients about the complexities of disease progression can promote realistic expectations and enhance their overall understanding of their condition.

Ultimately, patient education should aim to provide individuals with the knowledge and tools necessary to comprehend and navigate the intricacies of disease progression. By promoting patient understanding and involvement, health care providers can help mitigate anxiety and ensure that patients are equipped to actively participate in decisions regarding their treatment and care.

Provider Education

One of the key insights from the discussion pertains to the importance of education, particularly in the areas of adverse event monitoring and management. Faculty agreed that there is still a need for comprehensive education on how to effectively address and approach adverse events associated with treatments. A decade ago, there were instances in which patients may have experienced harm due to inadequate up-front management of these events. Furthermore, delays in administering appropriate therapies occurred when patients arrived at the emergency department without a wallet card containing crucial treatment information about their treatment for NSCLC. Hence, ongoing education efforts to enhance patient safety and ensure timely access to the appropriate treatments in the event of emergencies is critical.

A crucial aspect of education in the medical field is understanding of the importance of collaborating and seeking expertise beyond one’s own specialty. It is essential for medical oncologists to recognize that comprehensive patient care often requires a multidisciplinary approach. When navigating complex cases involving rheumatological or other types of conditions, it is prudent to partner with rheumatologists or other specialists who possess the necessary expertise. By engaging in collaborative efforts, medical oncologists can benefit from the guidance and insights of these specialists, ensuring optimal patient management. This collaborative approach extends to other disciplines as well, including departments of pulmonology and gastroenterology. Collaborating with colleagues who have specialized expertise is crucial for providing well-rounded care to patients. By fostering these interdisciplinary relationships, medical oncologists can navigate challenging scenarios more confidently, even when treating patients with complex comorbidities or other unique patient circumstances. It is important to overcome any hesitations or fears and embrace the multidisciplinary nature of health care for the benefit of patients.

Closing Remarks

The treatment landscape of NSCLC has undergone significant advancements in recent years. The emergence of immunotherapies and targeted therapies has expanded treatment options, providing improved outcomes for patients. The identification of biomarkers such as PD-L1 and driver mutations has allowed for personalized treatment approaches, which helps to ensure that patients receive the most effective therapies. However, challenges persist in areas such as assessing progression, monitoring adverse events, and determining the optimal duration of therapy. Education and collaboration among health care professionals—including oncologists, rheumatologists, and pulmonologists—are crucial in navigating these challenges and delivering comprehensive care to patients. Ongoing research and clinical trials continue to shape the future of NSCLC management, with the goal of refining treatment strategies, enhancing patient outcomes, and ultimately finding a cure for this complex disease. By prioritizing education, patient empowerment, and multidisciplinary collaboration, we can continue to improve the quality of care and make significant strides in the management of NSCLC.

References

1. American Cancer Society. Cancer Facts & Figures 2023. Accessed May 19, 2023 https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2023/2023-cancer-facts-and-figures.pdf
2. Basumallik N, Agarwal M. Small Cell Lung Cancer. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 12, 2022.
3. National Cancer Institute. Non-Small Cell Lung Cancer Treatment. Updated February 17, 2023. Accessed May 19, 2023. https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq
4. National Comprehensive Cancer Network. Non-Small Cell Lung Cancer (Version 3.2023).
   https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed May 19, 2023.
5. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231